Delivering on a Promise: Nanoparticles Carry siRNA to Tumours

But finding a way to deliver short stretches of RNA to tumors safely and effectively has been challenging. By themselves, small interfering RNAs (siRNAs) break down quickly and invade tumors poorly, so they need a delivery vehicle.

Now one exciting technology is enabling another. Scientists have successfully targeted cancer cells in mice by creating tumor-penetrating nanoparticles to carry siRNAs as their cargo.

In two papers published online Aug. 15, Broad associate members Sangeeta Bhatia and William Hahn reveal how they combined nanotechnology – the science of manipulating materials at the molecular scale – with RNA interference to halt the activity of a gene that drives ovarian cancer. In the Science Translational Medicine paper, they reveal how they used nanoparticles to insert siRNA into ovarian cancer cells and halt the activity of a newly discovered gene that drives cancer. Nanoparticles ferried siRNAs into cells by binding them to protein fragments called peptides that can pass through tumor cell membranes. Once inside the cells, the siRNAs homed in on their target gene.

In the Cell paper, described in this Broad news story, they used the technique to block mutated genes that by themselves don’t cause cancer but make cancer cells more vulnerable. Their experiments in mice provided crucial proof of principle for a hypothesis first made almost 20 years ago when tumor suppressor genes were discovered.

“These are two examples using Sangeeta Bhatia’s technology to specifically target tumors in animals using RNAi,” said Bill, co-senior author of both papers, a medical oncologist at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School. “I think it has a lot of potential for opening up the long-sought path to deliver RNAi as a drug in people. Delivery has always been the problem.”

The genes Bill, Sangeeta, and their colleagues chose as targets are an example of how scientists can make sense of the genomic chaos caused by cancer. They trained their sights on genes identified by Project Achilles, a comprehensive catalog of genes that are essential for cancer cell survival.In the Science Translational Medicine paper, their target was a mutated form of ID4. When the gene was silenced by the siRNA nanocomplexes, ovarian tumors shrank. Armed with that knowledge, scientists can now focus on ID4 as a potential drug target without waiting years to genetically engineer a strain of mice with mutated ID4.

“What we did was try to set forth a pipeline where you start with all of the targets that are pouring out of genomics, and you sequentially filter them through a mouse model to figure out which ones are important. By doing that, you can prioritize the ones you want to target clinically using RNA interference, or develop drugs against,” said Sangeeta, co-author, professor of health sciences and technology and electrical engineering and computer science at MIT, and a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

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